The term epilepsy refers to a complex series of over 40 diverse disorders that affect 1-2% of the population (Engle, J. Jr. Epilepsy Research 1996 26:141-150; McNamara J. Neurosci. 1994 14(6):3413-3425; Charlier et al. Nature Genetics 1998 18(1):53-56). The International League against Epilepsy periodically revises the classifications and publishes the nomenclature used to describe reported epilepsy phenotypes (Epilepsy, Intnl League Coalition 1989 30(4):389-399). The most common seizure phenotypes observed are idiopathic or primary generalized epilepsy (PGE), in which abnormal electrical activity spreads across the entire cerebral cortex, and focal epilepsy in which abnormal electrical activity is restricted to one brain region, usually the temporal lobe (TLE). Although recent studies have successfully identified specific genetic mutations in some rare seizure phenotypes, those genetic influences that predispose humans to common epilepsy types such as TLE and PGE are complex and poorly understood. Genetic influences on epilepsy have been the subject of several recent reviews (Ferraro, T. N. and Buono, R. J. “Genetics of Epilepsy: Mouse and Human Studies” In Genetic Influences on Neural and Behavioral Functions. eds. Plaff et al. 1999 CRC Press, Boca Raton, Fla.; Szepetowski, P. and Monaco, A. P. Neurogenetics 1998 1:153-163).
Family and twin studies have provided insights regarding the genetic influences on both PGE and TLE (Berkovic et al. Annals of Neurology 1998 43(4):435-45; Berkovic et al. Annals of Neurology 1996 40(2):227-235; Callenbach et al. Epilepsia 1998 39(3):331-6; Jain et al. Seizure 1998 7(2):139-43; Miller et al. Genetic Epidemiology 1998 15(1):33-49). Concordance rates in monozygotic twins for certain PGE subtypes are reported to range between 65% and 95%, while concordance rates in dizygotic twins are reported at 15-30% (Stoffel, M. and Jan, L. Y. Nature Genetics 1998 18:6-8; Miller et al. Genetic Epidemiology 1998 15(1):33-49; Jain et al. Seizure 1998 7(2):139-43). Genetic influences in TLE phenotypes were documented more than 30 years ago and, more recently, in relatively benign idiopathic forms of TLE (Berkovic et al. Annals of Neurology 1996 40(2):227-235; Neubauer et al. Neurology 1998 51(6):1608-12; Bray, P. F. and Wiser, W. C. Pediatrics 1965 36:207-211; Bray, P. F. and Wiser, W. C. N. Engl. J. Med. 1964 271:926-933). These and other studies provide strong evidence for an inherited component to common forms of PGE and TLE. Since these disorders are not inherited in a simple Mendelian fashion, it appears that they arise from multiple gene mutations interacting with environmental factors. In addition, epidemiological evidence in humans demonstrates that relatives of probands with PGE or TLE are at increased risk for susceptibility to both generalized and focal epilepsy compared to individuals in the general population (Ottman et al. Archives of Neurology 1998 55:339-344), suggesting that different forms of epilepsy may share some susceptibility loci.
Linkage studies have lead to the identification of gene mutations that cause several rare epilepsy types and have suggested the chromosomal locations of genes related to a few more common epilepsy types. Juvenile myoclonic epilepsy (JME) has been the most studied of the PGE subtypes and evidence for linkage on chromosomes 6p and 15q have been reported (Greenberg et al. Amer. K. Medical Genetics 1988 31:185-192; Liu et al. Amer. J. Hum. Genet. 1995 57:368-381). In each case linkage data have been replicated in some independent patient groups (Weissbecker et al. Am. J. Human Genetics 1991 38:32-36; Elmslie et al. Human Molecular Genetics 1997 6(8):1329-1334), but not others (Whitehouse et al. Am. J. Hum. Genet. 1993 53:652-662; LeHellard et al. Epilepsia 1999 40(1):117-9; Sander et al., Am. J. Med. Genetics 1999 88(2):182-7), suggesting that several loci are involved in predisposition toward JME, most likely including loci on human 6p and 15q. Linkage on chromosome 8q has been reported for common subtypes of idiopathic generalized epilepsy such as childhood absence or juvenile absence, but not replicated in all patient groups tested (Zara et al. Human Molec. Genetics 1995 4(7):1201-1207; Durner et al. Am. J. Hum. Genet. 1999 64(5) :1411-9; Fong et al. Am. J. Hum. Genet. 1998 63(4) :1117-29; Sander et al. published the largest linkage study to date on a collection of European patients and family members with generalized epilepsy including JME, CAE, and Juvenile Absence Epilepsy (JAE) (Hum. Molec. Genet. 2000 9(10):1465-1472). The results from this study provide evidence for a susceptibility locus on human chromosome 3q. This location was not previously reported in any other linkage study. Furthermore, the results did not replicate any evidence for linkage to 6P), 15q or 8q as previously reported by others (Greenberg et al. Amer. J. Med. Genet. 1988 31:85-92; Liu et al. Amer. J. Hum Genet. 1995 57:368-381; Weissbecker et al. Am. J. Hum. Genet. 1991 38:32-36; Elmslie et al. Hum. Molec. Genet. 1997 6(8):1329-1334). Thus the heterogeneity of the common epilepsy types continues to confound the search for seizure susceptibility factors.
Rare epilepsy types following Mendelian inheritance in families have lead to the identification of specific gene mutations that can cause seizure disorder in humans. Progressive myoclonic epilepsy (PME), a PGE subtype, shows linkage to markers on human chromosomes 6q and 21q (Serratosa et al. Hum. Molec. Genet. 1995 4(9):1657-1663; Sainz et al. Am. J. Hum. Genet. 1997 61(5):12-5-1209; Lehesjoki et al. Proc. Natl Acad. Sci. USA 1991 88(9):3696-9). PME of the Unverricht-Lundborg type was traced to a mutation in the gene encoding the protease cystatin B on 21q. PME of the Lafora type was traced to a mutation in the gene encoding a novel tyrosine phosphatase on 6q (Pennacchio et al. Science 1996 271:1731-4; Minassian et al. Nature Genetics 1998 20(2):171-4; Serratosa et al. Hum. Molec. Genet. 1999 8(2):345-52). Other PGE subtypes such as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and benign familial neonatal convulsions (BFNC) are linked to markers on human chromosomes 8q, and 20q (Lewis et al. Am. J. Hum. Genet. 1993 53:670-675; Wallace et al. J. Med. Genet. 1996 33(4):308-312; Leppert et al. Nature 1989 337:647-648; Phillips et al. Nature Genet. 1995 10(l):117-123). Mutations in two potassium ion channel genes (KCNQ2 and KCNQ3) have been identified as the BFNC loci on human chromosomes 8q and 20q (Biervert et al. Science 1908 279:403-406; Charlier et al. Nature Genetics 1998 18(1):53-56; Singh et al. Nature Genetics 1998 18(l):25-30); Stoffel, M. and Jan, L. Y. Nature Genetics 1998 18:6-8). In addition mutations in a nicotinic acetylcholine receptor alpha -4 subunit (CHRNA4) on 20q have teen linked to ADWFLE (Steinlein et al. Nature Genetics 1995 11(2):201-203: Steinlein et al. Hum. Molec. Genet. 1997 6(6):943-7) and mutations in a sodium ion channel SCN1B on 19q have recently been linked to generalized epilepsy with febrile seizures (GEFS, Wallace et al. Nature Genetics 1998 19:366-70). Partial epilepsy types are associated with regions on human chromosomes 2q, 10q and 15q (Scheffer et al. Annals of Neurology 1998 44(6):890-9; Ottman et al. Nature Genetics 1995 10:50-60; Poza et al. Annals of Neurology 1999 45(2):182-8; Neubauer et al. Neurology 1998 51(6):1608-12) and linkage on Xq and 8p has been detected in rare forms of epilepsy accompanied by mental retardation (Gendrot et al. Clinical Genetics 1994 45(3):145-153; Ryan et al. Nature Genetics 1997 17:92-95: Ranta et al. Genome Res. 1996 6(5):351-360). Finally there are additional reports of linkage on 19p for a familial form of febrile seizures (Johnson et al. Hum. Molec. Genet. 1998 7(1) :63-67) and 19q for benign familial infantile convulsions (Guipponi et al. Hum. Molec. Genet. 1997 6(3):473-477).
Although linkage studies have suggested the locations of genes for the common epilepsy forms such as JME, CAE, and TLE, these forms exhibit a high degree of clinical heterogeneity and the inheritance patterns are non-Mendelian, suggesting that multiple gene influences are responsible for most common seizure phenotypes. Alternative approaches are needed to help identify genes of partial effect in these common epilepsy types and to supplement the linkage work already accomplished and in progress.
One such alternative is to analyze epilepsy candidate genes for variations and then to demonstrate association of disease with inheritance of specific gene variants. This strategy has already been shown to be useful since a variation in a kainate type glutamate receptor is reported to be inherited in patients with idiopathic generalized epilepsy more often than predicted by classical genetics. (Sander et al. Am. J. Med. Genet. 1997 74:416-421)
Using a mouse model for epilepsy (Ferraro et al. Mammalian Genome 1997 8:200-208) , a susceptibility gene for seizures induced by various mechanisms was localized to a small region of murine chromosome 1 (Ferraro et al. J. Neuroscience 1999 19(16):6733-6739).
A sequence variation has now been identified in the homologous human gene, KIR 4.1. Further, it has now been determined that this variation occurs more frequently in epilepsy patients compared to matched controls.